2-carboxymethyl 4-oxo-tetrahydro-naphthalenes



United States Patent This application is a division of our copending application Serial No. 821,093, filed June 18, 1959, now US. Patent No. 3,102,914, which in turn is a continuation-inpart of our then copending application Serial No. 748,613, filed July 15, 1958, now abandoned.

This invention relates to new organic compounds and, more particularly, is concerned with novel 2-carboxymethyl-4-oxo-tetrahydronaphthalenes which may be represented by the following general formula:

C/H at wherein X is halogen or hydroxy, R is hydrogen or lower alkyl, and R is halogen. Suitable lower alkyl groups contemplated by the present invention are those having up to about 6 carbon atoms. Halogen is exemplified by bromine and chlorine.

The novel compounds of the present invention may be prepared by a series of reactions which involve ring closing a 3-benzylglutaric acid of the formula:

wherein R and R are as hereinbefore defined. The ring closure is effected-with a suitable condensing agent such as polyphosphoric acid or a mineral acid such as sulfuric acid. These novel tetrahydro-4-oXo-naphthalene-2-acetic acids have the formula:

wherein R and R are as hereinbefore defined.

The 3-benzylglutaric acids are also new compounds.

but are not claimed herein as they form part of the subject matter of the copending application of Raymond G.

Wilkinson et 211., Serial No. 748,589, filed July 15, 1958, now United States Patent No. 3,013,069.

The tetrahydro-4-oxo-naphthalene-Z-acetic acids, prepared as above described are then converted to the corresponding acyl halides by treatment with an agent such as oxalyl chloride, phosphorus pentachloride, phosphorus pentabromide, thionyl' chloride, thionyl bromide, and the like. The acyl halides so formed may then be converted to useful aldehyde products by a suitable reduction process. Catalytic hydrogenation has been found efiective in achieving this step. Gaseous hydrogen and a suitable catalyst such as a noble metal catalyst, e.g., palladium on charcoal, is preferably used. The reaction is preferably carried out in an inert organic solvent such as benzene, toluene, xylene and the like at temperatures ranging from about C. to about C.

The aldehyde products are biologically active and have been found to possess antifungal activity. The antifungal spectrum of the aldehydes, representing the amount required to inhibit the growth of various typical fungi, was determined in a standard manner by the agar dilution streak technique. The minimal inhibitory concentrations, expressed in milligrams perf'milliliter, of 'two typical aldehydes against various test organisms is set forth in Table I below:

TABLE 1 The novel compounds of the present invention are also highly useful intermediates for the preparation of substituted trioxo-octahydroanthracenes and octahydronaphthacenes described and claimed in the copending application of Raymond G. Wilkinson et al., Serial No. 790,051, filed January 30, 1959, now United States Patent No. 3,002,993. As described in detail in this application, the tetrahydro-4-oXo-naphthalene-Z-acetic acids of this invention can be converted to the corresponding acyl halides by treatment with a suitable agent such as oxalyl chloride, or alternatively, can be converted to a mixed carboxylic-carbonic anhydride derivative. Diethyl malonate is thenacylated and the resultant acyl malonate cyclized to the octahydrointhracene. The octahydroanthracene can be treated to removethe carbethoxy group or can be converted to 2-carboxamido-octahydroanthracene 'by first treating with alcoholic ammonia at 701l0 in a sealed vessel followed by strong acid hydrolysis.

The resulting products have the following general formula:

(mt ll y i i i i i 3 The novel compounds of the present invention may also be used to prepare novel tetracyclic compounds represented by the following general formula:

ORK: g (I) wherein R and R are as hereinabove defined, R is hydrogen or lower alkyl, and R is hydrogen, cyano or COOZ wherein Z is lower alkyl, mononuclear aryl or mononuclear aralkyl. Suitable lower alkyl and lower alkoxy groups are those having up to about 6 carbon atoms. Suitable aralkoxy groups are benzyloxy, phenethoxy, etc. Suitable mononuclear aralkyl substituents are benzyl, phenethyl, phenylpropyl, phenylbutyl, etc. and suitable mononuclear aryl substituents are exemplified by phenyl and substituted phenyl, suitable substituents on the phenyl ring being -Cl, Br, I, NO and lower alkyl radicals containing from 1 to 4 carbon atoms. Halogen is exemplified by chlorine and bromine.

In order to prepare the novel tetracyclic compounds represented by the above formula, the tetrahydronaphthaleneacetic acid is first converted to the correspondmg acyl halide by treatment with an agent such as oxalyl chloride. The intermediate acyl halide so formed is then converted to the desired naphthaleneacetaldehyde by a suitable reduction process. The aldehyde so formed is then treated with cyanoacetamide to form the corresponding dicyano glutaramide, which product is hydrolyzed in hydrochloric acid in the conventional manner. The glutaric acid is then subjected to a two-step methylation and the resulting product is treated with sodium hydride to form the corresponding octahydroanthraceneacetate. This product is then brominated to formfthe appropriate bromoketone which is treated with boiling collidine to form the corresponding naphthol. This latter product is methylated with postassium carbonate and dimethyl sulfate. The tricyclic acid is obtained by alkaline hydrolysis and is then treated with oxalyl chloride, or alternatively with ethyl chloroformate, and then with malonic ester and finally with sodium hydride to form the desired tetracyclic ester.

The invention will be described in greater detall 1n conjunction with the following specific examples.

Example 1.Preparation of 8-chl0r0-5-mth0xy-4-0xo- 1,2,3,4-tetrahydronaphthnlene-Z-acetic acid 94.0 grams (0.6 mole) of 2-chloro-5-methoxytoluene [Peratoner and Condorelli, Gazz. Chim. Ital. 28, I, 213 (1898)] are added to 600 milliliters of reagent grade carbon tetrachloride, 117.4 grams (0.66 mole) of N- bromosuccinimide and 0.1 gram benzoyl peroxide. The reaction mixture is stirred at reflux temperature and additional 0.1 gram quantities of benzoyl peroxide are added after 1 /2 and 18 hours. After 21 hours the volume of solvent is reduced to approximately 250 milliliters and the succinimide filtered off. The filtrate is washed with three 200 milliliter portions of water, dried over anhydrous MgSO and filtered. The solvent is removed under reduced pressure and the residual oil crystallized on standing overnight. Yield of crude 2-chloro-5- methoxybenzyl bromide, 131.0 grams. The pure compound crystallizes from (-40) petroleum ether as white needles, melting point 55.5-57.5" C.

131.0 grams (0.55 mole) of 2-chloro-5-methoxybenzyl bromide in 300 milliliters of absolute ethanol is added over a 1 hour period to a refluxing solution of diethylmalonate (145 grams, 0.9 mole) and sodium methylate (32.4 grams, 0.6 mole) in absolute ethanol. The refluxing is continued for an additional 2 /2 hours and the reaction mixture concentrated to approximately half pressure. Diethyl 2-chloro-5-methoxybenzyl-malonate is collected at 155-68/0.40.8 mm.; yield: 90.0 grams; 11 1.5030. Overall yield based on 2-chloro-5-methoxytoluene is 48% A solution of 105 grams (0.33 mole) of diethyl 2-chloro-S-methoxybenzylmalonate in 360 milliliters of dry ether is added slowly with stirring to 19.5 grams (0.513 mole) of LiA1H dissolved in 700 milliliters of dry ether. The mixture is stirred and refluxed for 4 /2 hours before decomposing the excess hydride with ethyl acetate. The mixture is acidified with 6 N HCl, washed with water, and allowed to stand over milliliters of 5 N NaOH over the weekend. The ether layer is washed with H O, dried over MgSO and concentrated to an almost colorless oil which turns to a mushy solid on seeding. Distillation at 0.1 mm. gives 64 grams (84%) of a colorless oil at 160-175 with a small forerun at On seeding, the main fraction gives white crystals of 2-(2'-chloro-5'-methoxybenzyl)-1,3-propanediol, melting point 41-46 C.

A solution of 2-(2'-chloro-5'-methoxybenzyl) 1,3 propanediol (100 grams, 0.435 mole) in 500 milliliters benzene and pyridine grams, 1.2 moles) is cooled to 5 C. Methanesulfonylchloride (114 grams, 1.0 mole) is added over a thirty minute period, the temperature of the reaction mixture being maintained between 5-15 C. The reaction mixture is stored at 5 for 16 hours. The precipitated white crystals are collected on a filter and washed thoroughly with five milliliter portions of benzene. The combined washings and filtrate are washed with 250 milliliters 1 N sodium bicarbonate, then with 200 milliliters of water. The benzene layer is treated with Norit, dried with anhydrous magnesium sulfate and the volatile solvent removed in vacuo. Yield of crude 2-(2-chloro-5-methoxybenzyl) 1,3 propanediol, bis-methane sulfonate is 172.3 grams. Recrystallization of 148 grams of the crude material from 300 milliliters of n-butanol yields 135.0 grams of white crystals. Melting point. 75-77 C. (93.7%).

A solution of potassium cyanide (47.7 grams, 0.765 mole) in 230 milliliters of water is added to a solution of 2 (2'-chloro-5-methoxybenzyl)-1,3-propanediol, bismethane sulfonate (135.0 grams, 0.348 mole) in 690 milliliters of ethanol. The reaction mixture is refluxed on a steam bath for 4.5 hours, during which time it changes from light yellow to dark green. A 230 mi1liliter portion of 10 N sodium hydroxide is then added and refluxing continued for an additional 16 hours. At the end of this period, the solution has completely lost its green color and is amber. The solution is concentrated to approximately 600 milliliters by distillation at atmospheric pressure and then extracted with three 300 milliliter portions of ether. The aqueous layer is treated with Norit and filtered; the filtrate cooled to 10 and acidified by the slow addition of 200 milliliters concentrated hydrochloric acid. The white solid which precipitates is collected on a filter and then dissolved in 350 milliliter of fi-(2-chloro 5-methoxybenzyl)-glutaric acid (60.0 grams,

0.21 mole). The reactants are thoroughly mixed at room temperature and then heated at 50-60 for two hours with intermittent stirring The reaction mixture turns a light yellow almost immediately, gradually darkens, to

a tannish yellow. After two hours the reaction mixture is slowly poured into six liters of cool water with vigorous stirring. After storing at 5 for 14 hours the white crystals are collected on a filter, washed with four 250 'to stand at room temperature for two days. The white crystals which separate are collected on a filter and dried in vacuo over P Yield of pure material 41.4 grams (73.3%). Melting point, 139-196 C.

Example 2.-Preparation 0 f 8-chl0r0-5-meth0xy-4-0x0- J,2,3,4-tefrahydro-naphthalene-Z-acetyl chloride Five milliliters of oxalyl chloride in 50 milliliters ben- Zone is added dropwise, over a thirty minute period, to a refluxing suspension of 5.4 grams (0.020 mole) of 8- chloro-S-methoxy -4- oxo 1,2,3,4-tetrahydronaphthalene- Z-acetic acid in 50 milliliters benzene. The reaction mix- I ture is refluxed an additional thirty minutes after all the oxalyl chloride is added. The esultant dark brown solution is concentrated to a dark brown oil in vacuo. A

- portion of the crude acid chloride is taken up in 40 mil- Example 3.Pre paration of 8-chl0r0-5-meth0xy-4-oxm 1,2,3,4-tetrahydronaphthalene-Z-acetaldehyde 1.08 grams of 8-chloro-5-methoxy-4-oxo-1,2,3,4-tetrahydronaphthalene 2 acetic is added to milliliters of anhydrous benzene. The suspension is brought to reflux with stirring, and a solution of 1.0 milliliter oxalyl chloride in 10 milliliters anhydrous benzene added dropwise over a period of 30 minutes. The solution is kept at reflux for'an additional 30'minutes and allowed to cool. The liquid is then evaporated in vacuo at room temperature to give the oily acid chloride. The acid chloride is redissolved in 40 milliliters of anhydrous toluene, then 0.30 gram of 10% palladium on charcoal is introduced. The system is swept with nitrogen, then a slow stream of hydrogen is introduced and maintained. The mixture is stirred and heated to reflux in the hydrogen stream for two hours. The hydrogen stream is replaced by nitrogen and the solution allowed to cool. The catalyst is removed by filtration and Washed with additional solvent. The combined filtrates are diluted with some ether, then washed thoroughly with sodium bicarbonate solution, then with water, and dried over sodium sulfate; Evaporation of the solvent gives an oil which is crystallized from ether to give 382 milligrams of cream colored 8-chloro- 5-methoxy-4-oxo-1,2,3,4 tetrahydronaphthalene-Z-acetaldehyde, melting point 90-9l C.

Example 4 .Preparation of 8-chl0r0-5-hydroxy-4-0xo- Z,2,3,4-tetrahydronaphthalene-Zacezaldehya'e A mixture of 1.08 grams of.8-chloro-5-hydroxy-4-oxo- 1,2,3,4-tetrahydronaphthalene-Z-acetic acid prepared by refluxing 8 chloro-5methoxy-4-oxo-1,2,3,4 tetrahydronaphthaleneacetic acid with 48% aqueous hydrobromic acid for one hour, and 10 milliliters ofanhydrous benzene are brought to reflux temperature. To the boiling solution is added, dropwise over a period of minutes, 0.9 gram oxalyl chloride in 5 milliliters anhydrous ben- The mixture is contacted with a the mixture is brought to reflux with vigorous stirring.

barium sulfate added. Hydrogen is passed zen e. The solution isrefluxed foran additional minutes and allowed to stand at room temperature for 15 hours.

The solution is then freed from solvent on the vacuum line. The resulting pale yellow oily acid chloride is redissolved in suflicient anhydrous benzene to make 3.5 milliliters of solution. One milliliter of this solution is added to 15 milliliters of anhydrous toluene containing milligrams of 10% palladium-on-charcoal. stream of hydrogen and After two hours the hydrogenation is discontinued and the solution allowed to cool. The catalyst is removed by filtration and washed with benzene. The combined filtrates are diluted with ether then washed thoroughly with sodium bicarbonate solution, then with water and dried over sodium sulfate to yield on crystallization from pctroleum ether, 87 milligrams of colorless 8-chloro-5- hydroxy-4-oxo 1,2,3,4 tetrahydronaphthalene-2-acetaldehyde, melting point 64-65 C.

Example 5 .-Preparati0n of 8-chl0r0-5-methoxy-4-0x0- 1,2,3,4-tetrahydr0nlzphthalene-Z-actaldelWde A solution of oxalyl chloride (5 milliliters) in benzene (25 milliliters) is added dropwise, over a thiry-minute period, to a refluxing suspension of 8-chloro-5-methoxy- 4-oxo 1,2,3,4 tetrahydronaphthalene-Z-acetic acid (5.4 grams, 0.020 mole) in benzene (50 milliliters). The reaction mixture is refluxed an additional thirty minutes after all of the oxalyl chloride is added. The resultant dark brown solution is concentrated to dryness in vacuo and the crude acid chloride dissolved in 400 milliliters of toluene. The solution is filtered and 1.0 gram of 5% palladium on through at a vigorous rate and the solution is refluxed. After 155 minutes, 65% of the theoretical amount of hydrogen chloride is evolved. An additional 1.0" gram of 5% palladium on barium sulfate is added. After an additional 113 minutes 9095%' of the theoretical amount of hydrogen chloride is evolved. The system is flushed with nitrogen, cooled and the catalyst filtered off. The toluene solution is washed with three milliliter portions of 1N sodium bicarbonate solution and three times with 50 milliliter portions of water. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a tan solid in vacuo. The crude aldehyde is slurried in 100 milliliters of ether'and the cream colored crystals are collected on a filter and air-dried. The yield of 8 chloro-5-methoxy-4-oxo-1,2,3,4-tetrahydronaphthalene-2-acetaldehyde is 2.82 grams, melting point 89-91 C.

The following example illustrates the transformation of the tetrahydro-4-oxo-naphthalene-Z-acetic acids of this invention to substituted trioxo-octahydroanthracenes' as described in the aforesaid copending application of Raymond G. Wilkinson et al., Serial No. 790,051.

Example 6.Preparati0n 0y 2 carb0xamid0-5-chl0r0-8- meth0xy-1,3,9 trioxo-Z,2,3,4,4a,9,9a,10 octahydroanthracene 8-chloro-5-methoxy-4-oxo 1,2,34 tetrahydronaphthalene-Z-acetic acid (10.8 grams 0.040 mole) is suspended in 50 milliliters of sodium dried benzene. The suspension is refluxed and a solution of oxalyl chloride (6.42 milliliters 0.080 mole) in 50 milliliters of sodium dried benzene is added dropwise over a thirty minute period. A clear yellow solution forms as the. reaction proceeds. The solution is refluxed an additional thirty minutes and'then the excess oxalyl chloride and benzene are removed under reduced pressure. The oily resid ue is dissolyed in 25 milliliters of benzene and again concentrated to an oil under reduced pressure. The oily acid chloride is dissolved in 100 milliliters of sodium dried toluene. V The magnesium salt of diethyl malonate is prepared by heating magnesium metal (972.8 milligrams, 0.040 mole), carbon tetrachloride (0.3 milliliter), absolute ethanol (7.28 milliliters) and diethyl malonate (6.08 milliliters, 0.40 mole) intermittently on a steam bath for fifteen minutes, then 100 milliliters of sodium dried ether is added and refluxed with stirring until all of the magnesium is dissolved (approximately two hours). The ethereal solution of magnesiomalonic ester is cooled to room temperature and the toluene solution of the acid chloride prepared above is added dropwise, with stirring, over a thirty minute period. After seven minutes sodium chloride begins precipitating. After ten minutes the magnesium salt of the acylated malonic ester begins separating as a yellow gum. The reaction mixture is refluxed for twenty minutes after the addition of the acid chloride, is cooled to room temperature and sodium hydride added (4.0 grams, 0.160 mole). An additional 200 milliliters of sodium dried toluene is added and the ether removed by distillation. The reaction mixture is then refluxed for seventeen hours. The dark brown suspension is cooled to room temperature and 10 milliliters of absolute ethanol added to decompose the excess sodium hydride. The reaction mixture is mechanically shaken for one hour with 200 milliliters of 1 N HCl, the toluene layer separated, washed twice with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a syrupy residue and 50 milliliters of absolute ethanol added. The mixture is heated on a steam bath and allowed to slowly cool to room temperature. Brownish yellow crystals of crude cyclized product are deposited. Yield 4.97

grams (34%), M.P. 15964 C. 4.68 grams of the crude are recrystallized from 200 milliliters of absolute ethanol and 20 milliliters of dimethylformamide, yielding 3.72 grams of the pure octahydroanthracene (26.7%), M.P. l64-7 C.

A suspension of Z-carbethoxy-S-chloro-8-methoxy- 1,3,9-trioxo-1,2,3,4,4a,9,9a,l-octahydroanthracene (1.0 gram, 0.00276 mole) in 25 milliliters of absolute methanol contained in a stainless steel bomb is cooled to 0 C. and saturated with anhydrous ammonia. The bomb is sealed, heated at 80 for five hours and then allowed to stand at room temperature overnight. The methanol is evaporated off under an air jet at room temperature and the residue slurried in 10 milliliters of 1 N NaOH. The tan solid is collected on a filter and then heated in 10 milliliters of ethanol. The insoluble portion is collected on a filter and dried in vacuo over P 0 to yield 350 milligrams of crude product. 150 milligrams of this material is heated on a steam bath for ten minutes with 15 milliliters of 4 N HCl. The yellow crystals are collected and recrystallized from a dimethylformamidewater mixture, yielding 65 milligrams of 2-carboxamido- 5-chloro-8-methoxy-3-(or 1- or 9-)imino-l,9-dioxo-1,2,3, 4,4a,9,9a,10-octahydroanthracene, M.P. 194-l97 C. with dec.

Crude 2-carboxamido-5-chloro-8-methoxy-3-(or 1- or 9-)imino-1,9-dioxo 1,2,3,4,4a,9,9a,10 octahydroanthracene (100 milligrams) is heated on a steam bath with 5 milliliters of 4 N HCl for three hours and then allowed to stand at room temperature for an additional three hours. The reaction mixture is filtered and the crude amide recrystallized from a dimethylformamide-ethanol mixture, yielding 55 milligrams of pure Z-carboxarnido-S- chloro-8-methoxy-1,3,9-trioxo-1,2,3,4,4a,9,9a,10 octahydroanthracene, M.P. 239-241 C. dec.

The following example illustrates the transformation of the tetrahydro-4-oXo-naphthalene-2-acetaldehydes to octahydronaphthacenes as described in the aforesaid copending application of Raymond G. Wilkinson et al., Serial No. 790,051.

Example 7.Preparati0n of ethyl 10-benzyloxy-7-chl0ro- J1 methoxy-1-3-1Z-trioxo-I,2,3,4,4a,5,12,12a octahydronaphthacene-Z-carb0xylate Cyanoacetamide (8.0 grams, .095 mole) and 8-chloro- 1,2,3,4 tetrahydro-5-methoxy-4-oxo-2 naphthaleneacetaldehyde are dissolved in absolute ethanol (300 milliliters) with the aid of heat. The solution is cooled, filtered,

five drops of piperidirie added and the liquid is allowed to stand at room temperature for 24 hours. The white crystals (11.7 grams, 92%) which deposit are collected by suction filtration, washed with ether, and air-dried. This highly insoluble product has a melting point of 140155 C., but the melting point of other batches run in a similiar manner varies from to 160, despite constant analyses.

2,2'- dicyano-3-(8-chloro-1,2,3,4-tetrahydro-5-methoxy- 4-oxo-2-naphthylmethyl)glutaramide (10.0 grams, 0.0249 mole) is slurried in a mixture of concentrated hydrochloric acid (405 milliliters) and glacial acetic acid milliliters). Upon refluxing a clear yellow solution forms which gradually turns bright red then brown. After twelve hours the reaction is cooled and filtered. The filtrate is concentrated in vacuo to approximately twothirds volume. The light yellow crystals which separate are collected on a filter, washed thoroughly with water and dried in vacuo' over phosphorous pentoxide and potassium hydroxide pellets. Yield of the glutaric acid is 5.9 grams (70%), M.P. 177S0 C. Recrystallization from ethyl acetate raises the melting point to 181.5482".

3 (8-chloro-1,2,3,4-tetrahydro-5-hydroxy-4-oxo-naphthylmethyl)glutaric acid (0.920 gram, 0.0027 mole) is dissolved in 25 milliliters of 1 N sodium hydroxide. Benzyl chloride (1.8 grams, 0.0142 mole) is added and the mixture refluxed for two hours under nitrogen. The reaction is cooled and extracted with five 2O milliliter portions of ether. The aqueous layer is separated, acidified and the tan oily solid which separates is extracted into ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtcred and concentrated to a light tan solid in vacuo. Crude 3-(5-benzyloxy-8- chloro 1,2,3,4-tetrahydro-4-oxo-naphthylmethyl)glutaric acid (1.1 grams) is obtained. An analytical sample is obtained from ethyl acetate as a colorless microcrystalline solid, M.P. 174-176 C.

Crude 3-(5-benzyloxy-8-chloro-l,2,3,4-tetrahydro-4-oxo- Z-naphthylmethyl)glutaric acid (1.1 grams, 0.0024 mole) is dissolved in 50 milliliters of methanol and 1 drop of concentrated sulfuric acid is added. The solution is refluxed on a steam bath for 2 hours, concentrated in vacuo to approximately 8 milliliters and diluted with S0 milliliters of ethyl acetate. The ethyl acetate solution is washed thrice with 20 milliliter portions of 1 N sodium bicarbonate and thrice with 20 milliliter portions of water. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to an oily residue in vacuo. Yield of crude dimethyl 3-(5-benzyloxy- 8-chloro-1,2,3,4 tetrahydro 4 oxo-naphthylrnethyl) glutarate is 1.0 gram. Recrystallization of crude diester from ether-petroleum-ether produces an analytical sample, colorless crystals, M.P. 6263 C.

Dimethyl 3-(5 benzyloxy 8 chloro 1,2,3,4 tetrahydro 4 oxo naphthylrnethyl)glutarate (1.73 grams, 0.0037 mole) is dissolved in 100 milliliters of toluene. Sodium hydride (230 milligrams, 0.010 mole) is added and the mixture refluxed under nitrogen for 4.5 hours, cooled to room temperature and allowed to stand overnight. Additional sodium hydride milligrams, 0.0063 mole) is added and the reaction is refluxed 1.5 hours. The excess hydride is decomposed by the addition of 2 milliliters of methanol. The solution is diluted with 50 milliliters of chloroform, washed twice with 25 milliliter portions of 1 N hydrochloric acid and twice with 25 milliliter portions of water. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated to an oily residue in vacuo. The residue is dissolved in 50 milliliters of ether and 80 milliliters of hexane added. Upon standing at 5 C. overnight small White crystals are deposited. The yield of methyl-S-benzyloxy-S-chloro-1,2,3,4,4a,9,9h,10- octahydro-4,10-dioxo-2-anthraceneacetate is 495 milligrams, M.P. l00105 C. Work-up of the filtrate yields an additional 200 milligrams of the desired product.

Total yield of crystalline material is 44% of theory. Repeated recrystallization of crude product from ether raises the M.P. to 117-121 C.

Crystalline methyl -benzyloxy-8-chloro-1,2,3,4,4a,9, 9a,10 octahydro 4,10 dioxo 2 anthraceneacetate (6.5 grams) is dissolved in a mixture of ethyl acetate (40 milliliters) and glacial acetic acid (80 milliliters). Anhydrous sodium acetate powder (1.75 grams) is added and the mixture stirred magnetically until a solution is obtained. The reaction vessel is cooled to 05 and to the contents are slowly added, with stirring, 16 milliliters of a 1M solution of bromine in glacial acetic acid. The entire reaction mixture is poured into benzene, the benzene solution washed with salt solution containing a little sodium sulfite, then with four successive portions of water. The benzene layer is dried over magnesium sulfate and the solvent removed to give the crude bromoketone (7.0 grams) as a pale pink foam.

The bromoketone is dissolved in 45 milliliters freshly distilled collidine and the solution heated under nitrogen at reflux for 12 minutes. The cooled supernatant is separated from solid collidine hydrobromide by decantation, the solid washed with ether-benzene and the ether and collidine solutions combined. The extracts are washed with ice-cold 3 N sulfuric acid until the collidine odor is no longer present. The organic extracts are dried over magnesium sulfate and the solvent evaporated in vacuo. There remain 5.5 grams (84%) of methyl 5 benzyloxy 10 hydroxy 8 chloro 1,2,3, 4-tetrahydro-4-oxo-2-anthraceneacetate. The analytical sample is obtained from ether, M.P. 132-134 C.

To a solution of the above product and dimethyl sulfate (3.2 milliliters) in anhydrous toluene (160 milliliters) is added micronized anhydrous potassium carbonate (33 grams, previously dried 12 hours at 130) and the stirred suspension held at reflux for six hours. The cooled mixture is filtered through a sintered-glass suction funnel and the filter cake (K CO washed with benzene. The combined filtrates are reduced to 30 milliliters in vacuo and chromatographed over 100 grams of alumina. Eluates corresponding to (A) benzene to benzene-10% ethyl acetate and (B) benzene-% ethyl acetate to benzene-50% ethyl acetate are separately collected. Concentration and recrystallization of the residues from ether gives from (A) 0.80 gram of yellow needles, M.P. 129130 C.; from (B) 1.24 grams tan needles, M.P. 127l28 C.; mixed M.P. 127128.5 C.

A solution of 2.5 grams potassium hydroxide, 4 milliliters water and 35 milliliters methanol is brought to reflux and allowed to cool in a nitrogen atmosphere. To the cold solution is added methyl 5-benzyloxy-10-methoxy 8 chloro 1,2,3,4 tetrahydro 4 oxo 2 anthraceneacetate (1.17 grams), and the suspension brought to reflux under nitrogen. After one hour of reflux the solution is evaporated in vacuo to approximately one half the original volume. The reaction mixture is poured into excess ice-cold 1 N sulfuric acid and the organic product extracted into ethyl acetate. The ethyl acetate is washed twice with water and dried over magnesium sulfate. Evaporation of solvent gives 1.09 (96%) of crystalline tricyclic acid, tan needles melting at 169- 171 times from ethyl acetate to give straw-colored needles, M.P. l75-176 C. Solvent of crystallization is removed by drying at 100 in vacuum for four hours.

A suspension of 1.01 grams crystallized 5 benzyloxy 10 methoxy-8-chloro-1,2,3,4- tetrahydro-4oxo-2-anthraceneacetic acid in 50 milliliters C. The analytical sample is recrystallized three (2.3 millimoles) of re- 10 of anhydrous toluene is stirred magnetically at room temperature under a dry nitrogen atmosphere. Addition of tn'ethylamine (0.38 milliliter, 2.75 millimoles) effects solution of the acid. The mixture is cooled to 10 C. and ethyl chloroformate (0.26 milliliter, 2.75 millimoles) is added. The stirring at -10 C. under nitrogen is maintained for 15 minutes, at which time there is added 5.5 milliliters of 0.45 magnesio ethoxy diethyl malonate in toluene. The reaction mixture is allowed to stand at room temperature for 18 hours; it is then poured into excess cold 2 N sulfuric acid. The acylmalonate is extracted into benzene, the benzene extracts washed with sodium bicarbonate and water, dried over magnesium sulfate, and evaporated to leave 1.39 grams of product.

The acyl malonate (1.39 grams) is dissolved in 20 milliliters of toluene and evaporated to dryness in vacuo, then held at at 1 mm. vacuum for one hour. The dried acyl malonate is dissolved in 35 milliliters sodiumdried reagent toluene. To the solution is added sodium hydride in oil (1.20 grams of a solid suspension ca. 52% NaH by weight) and the stirred mixture refluxed under a nitrogen atmosphere for twenty-minutes.

The reaction mixture, which turns from the original very pale yellow to a strong golden-brown color, is cooled to room temperature and then cooled further in ice-water. The remaining sodium hydride is destroyed by the cautious dropwise addition of glacial acetic acid (3 milliliters) followed by the very slow addition of absolute ethanol. The resulting solution is poured into cold dilute sulfuric acid, the organic components extracted into ethyl acetate, and the extracts washed with sodium bicarbonate and water. After drying over magnesium sulfate the solvent is evaporated to leave an oil (which contains ca. 0.6 gram mineral oil from the Nail suspension). The oil is taken up in 35 milliliters dry ether and the solution scratched until crystallization commences. On standing of the solution in the icebox overnight there is obtained 415 milligrams (35%) of golden yellow crystals, M.P. 170l71 C. The analytical sample is recrystallized from ethyl acetate and dried at for four hours in vacuum; golden needles, M.P. 169 171 C.

What is claimed is:

1. A compound of the formula:

@jomoom wherein R is selected from the group consisting of chlorine and bromine, and R is selected from the group consisting of hydrogen and lower alkyl.

2. 8 chloro 5 hydroxy 4 oxo 1,2,3,4 tetrahydronaphthalene-Z-acetic acid. 1

3. 8 chloro 5 methoxy 4 oxo 1,2,3,4 tetrahydronaphthalene-Z-acetic acid. 

1. A COMPOUND OF THE FORMULA: 